BRCA1 Mutation Carrier Status Research Articles

Isoflavone intake on the risk of overall breast cancer and molecular subtypes in women at high risk for hereditary breast cancer.

We investigated the association between isoflavone (ISF) intake and hereditary breast cancer (BC) risk, particularly by molecular subtype, in East-Asian BRCA1/2 mutation carriers and non-carriers at a high risk of hereditary breast cancer (i.e., family historyof BC (FHBC) and early-onset BC [EOBC, age < 40years]). The association between ISF intake and BC risk by molecular subtypes was assessed in 1709 participants (407 BRCA1/2 carriers, 585 FHBC non-carriers, 586 EOBC non-carriers, and 131 unaffected non-carriers) from the Korean Hereditary Breast Cancer Study using hazard ratios (HRs) and 95% confidence intervals (CIs) in weighted Cox regression models. Daily ISF intake was assessed using a validated food frequency questionnaire. We evaluated gene-environment interactions between BRCA1/2 mutation and ISF intake in 1604 BC cases by calculating the case-only odds ratios (CORs) and 95% CIs in logistic regression models. ISF intake was inversely associated with luminal A BC risk in BRCA2 mutation carriers and FHBC non-carriers (HR = 0.14, 95% CI = 0.04-0.50 for high intake [ISF intake ≥ 15.50mg/day]; HR = 0.27, 95% CI = 0.11-0.69 for high intake, respectively). We observed a reduced risk of triple negative BC (TNBC) in BRCA1 carriers and FHBC non-carriers (HR = 0.09, 95% CI = 0.02-0.40 for high intake; HR = 0.19, 95% CI = 0.05-0.69 for high intake, respectively). In the case-only design, an interaction between BRCA1 mutation carrier status and ISF intake emerged in TNBC patients (COR = 0.39, 95% CI = 0.16-0.95). This study suggests that ISF intake is inversely associated with BC risk in women at high risk of hereditary BC and that the effect could differ by molecular subtypes.

Management and 5-Year Survival of BRCA1 -Associated Breast Cancer Patients

Aim: The aim of this study is to estimate survival of breast cancer patients associated with BRCA1 mutation in Lithuanian population. Materials &amp; methods: We studied the 5-year survival rates of familial breast cancer patients from unrelated families who had an aggregation of at least two or three breast cancers only; and a group comprising of consecutive, newly diagnosed patients unselected for age, sex or family history. The treatment of patients was similar, as per National protocols, for the treatment of breast cancer cases independent of mutation status. Results: The 5-year survival of familial and non-familial breast cancer patients BRCA1 founder mutation carriers is statistically similar to patients the mutation non-carriers: 90.00 and 89.19%; 76.92 and 86.19% respectively (p = 0.7730). Conclusion: The 5-year survival rates for breast cancer patients are not dependent on their BRCA1 mutation carrier status when identical management and treatment is received.

Triple-negative breast cancer frequency and type of BRCA mutation: Clues from Sardinia.

Germline mutations in BRCA1 or BRCA2 genes have been demonstrated to increase the risk of developing breast cancer. Among the prognostic factors currently used in clinical practice, the disease stage and the receptor status play a crucial role in the management of breast carcinoma. Triple-negative breast cancer (TNBC) has been classified as a disease subgroup that is negative for oestrogen, progesterone and HER2 receptor expression, and presents a poor prognosis. The present study investigated the correlation between BRCA1/2 mutations and TNBC status in a large series (n=726) of breast cancer patients from Sardinia. The BRCA mutation screening was performed on genomic DNA from peripheral blood samples by denaturing high-performance liquid chromatography analysis and automated DNA sequencing. Overall, 21/726 (2.9%) patients carried a germline mutation in BRCA1 or BRCA2. The TNBC phenotype was significantly associated with the BRCA1 mutations (P<0.001), whereas no association was found with the BRCA2 mutations (P=0.837). With respect to patient origin within Sardinia, a significant inverse distribution of mutations was found; BRCA1 and BRCA2 mutations represented 86 and 93% of the mutated cases in Southern and Middle-Northern Sardinia, respectively (P<0.001). Patients from the geographical area with BRCA1 mutation prevalence presented a TNBC incidence much higher than that observed in cases from the area with BRCA2 mutation prevalence (12 vs. 4%, respectively; P=0.037). These findings further confirmed that the occurrence of TNBC is significantly associated with the BRCA1 mutation carrier status and that a different ‘genetic background’ may have a phenotypic impact in the onset of breast cancer.

Abstract 2813: Vitamin D, calcium, and dairy intake and familial breast cancer

Abstract Background: There is substantial evidence that breast cancer aggregates within some families, accounting for about 25% of incident cases. Known genetic variants, such as BRCA1/BRCA2 mutations, account for less 25% of these familial breast cancer cases, and furthermore 15-30% of mutation carriers will never develop breast cancer. Thus, research into additional risk or protective factors for familial breast cancer may provide valuable information for risk stratification. There is accumulating epidemiological and experimental evidence that vitamin D, calcium, and dairy, are associated with sporadic breast cancer risk, however it is unknown whether these factors are also associated with familial breast cancer. Methods: To address this question, we conducted a case-control study of probands identified from the UCLA Family Cancer Registry; a population enriched with women with a strong family history of breast cancer and BRCA1/BRCA2 mutation carriers. This study included 612 unrelated women who developed breast cancer and 497 unaffected controls within the registry recruited between 1998 and 2006. All participants completed a detailed survey questionnaire that examined reproductive and lifestyle factors, various health and screening behaviors, as well as information on a variety of putative breast cancer risk or protective factors including vitamin D and calcium supplement use (yes or no) and dairy consumption (servings per day). Multivariate logistic regression models controlling for confounding factors were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of vitamin D, calcium, and dairy with familial breast cancer. Results: Cases and controls were similarly distributed by race (80% were non-Hispanic white) and BRCA1 mutation carrier status (12%), however cases on average were five years older than controls and were more likely to be BRCA2 mutation carriers (12% versus 6%). Vitamin D (OR=0.88, 95% CI=0.63-1.24), calcium (OR=0.73, 95% CI=0.56-0.67), and dairy (OR=0.81, 95% CI=0.65-1.01) were inversely associated with breast cancer in this population. These associations did not appear to be modified by BRCA1 or BRCA2 mutation status. For women with three affected first degree relatives, the breast cancer associations with vitamin D (OR=0.19, 95% CI=0.02-1.8) and calcium (OR=0.29, 95% CI=0.06-1.3) were considerably strengthened; however these associations were not statistically significant. No other vitamins (A, B, C, or E), supplements (herbal remedies), or dietary factors (fruits, vegetables, fiber, or fat) were significantly associated with breast cancer. Conclusion: Calcium supplementation was associated with familial breast cancer, independently of BRCA mutation status, and the vitamin D and calcium associations with breast cancer may be modified by family history. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2813.

Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic?

There is a strong association between BRCA1 mutation carrier status and estrogen receptor-negative breast cancer. This has led to the idea that estrogen receptor-positive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view.

Implications of the Age Range in a Population-based BRCA1 Testing Program with Eligibility Based on Family History of Breast and Ovarian Cancer

The current options available to BRCA1 mutation carriers can be classified as either cancer risk reduction or increased disease surveillance. Risk reduction might be preferable to young women. Increased surveillance might be more attractive to women when their cancer risk is highest. The aim of this report is to estimate the sensitivity, specificity and ability to detect carriers for a population-based BRCA1 testing program with eligibility based on family history of cancer, and examine the effect of age on the program's performance. A computer model was used to simulate the incidence of breast and ovarian cancer in a woman's family, based on her BRCA1 mutation carrier status. Age-specific estimates of the sensitivity and specificity for family history as an indicator of mutation status were applied to local population figures. Sensitivity of the program increased with the age of the proband and the size of her family. Sensitivity ranged from 0.33 for 20-year-olds with small families, to 0.98 for 60-year-olds with large families. Specificity was greater than 0.95, regardless of a woman's age or family size. If 0.12% of people carry a BRCA1 mutation, a province-wide testing program for people aged 20-69 with referrals based only on family history would have a sensitivity of 0.55. Only 2% of the genetic test results would be positive. The acceptability of a genetic testing program depends on its sensitivity and specificity, and on the options available to women who are found to carry a mutation. Compared with variation due to family size, the program sensitivity and specificity does not differ substantially amongst the various age groups.

Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome

The association between BRCA1 germ-line mutations and breast cancer prognosis is controversial. A historical cohort study was designed to determine the prognosis for women with axillary lymph node negative hereditary breast cancer. We tested pathology blocks from 118 Ashkenazi Jewish women with axillary lymph node negative breast cancer for the presence of the two common BRCA1 founder mutations, 185delAG and 5382insC. Patients were followed up for a median of 76 months. Somatic TP53 mutations were screened for by immunohistochemistry, and direct sequencing was performed in the BRCA1-positive tumours. Sixteen breast cancer blocks (13.6%) carried a BRCA1 mutation. Young age of onset, high nuclear grade, negative estrogen receptor status and over-expression of p53 were highly associated with BRCA1-positive status (P-values all <0.01). BRCA1 mutation carriers had a higher mortality than non-carriers (five-year overall survival, 50% and 89.6%, respectively, P = 0.0001). Young age of onset, estrogen receptor negative status, nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Cox multivariate analyses showed that only germ-line BRCA1 mutation status was an independent prognostic factor for overall survival (P = 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrier status was a significant prognostic factor of death (risk ratio 5.8, 95% confidence interval: 1.5-22, P = 0.009). Sequencing of BRCA1-related breast cancers revealed one TP53 missense mutation not previously reported in breast cancer. Using a historical cohort approach, we have identified BRCA1 mutation status as an independent prognostic factor for node negative breast cancer among the Ashkenazi Jewish women. Those managing women carrying a BRCA1 mutation may need take these findings into consideration. Additionally, our preliminary results, taken together with the work of others suggest a different carcinogenic pathway in BRCA1-related breast cancer, compared to non-hereditary cases.